Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer. One such drug, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit such enzymes as dihydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthetase.
More recently, a series of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives have been disclosed and shown to be particularly useful antifolate drugs. See, for example, U.S. Pat. Nos. 4,996,206; 5,028,608; 5,106,974; and 4,997,838. In the synthesis of these compounds, an important group of intermediates, 4- hydroxy-5-halo-pyrrolo[2,3-d]pyrimidine derivatives, are frequently synthesized and then reacted with the desired carboxylic acid derivative or L-glutamic acid derivative via conventional techniques.
However, the preparation of 4-hydroxy-5-halopyrrolo[2,3-d]pyrimidines by direct halogenation at the C-5 position of the corresponding 4-hydroxypyrrolo[2,3-d]pyrimidines has not been synthetically useful either because of poor regioselectivity, where halogenation frequently occurs at both the C-5 and C-6 positions, or because of the inconvenience of harsh, multi-step processes. See, for example, Cocuzza, A. J., Tetrahedron Letters, 29: 4061-4064 (1988); Gerster, et al., J. Het. Chem. 207-213 (1969); and U.S. Pat. No. 4,996,206. The present invention provides an improved process for direct halogenation of 4-hydroxypyrrolo[2,3-d]pyrimidines at the C-5 position.
The resulting compounds, 4-hydroxy-5-halopyrrolo[2,3-d]pyrimidines, are primarily useful as intermediates for the synthesis of antineoplastic glutamic acid derivatives. However, one of ordinary skill in the organic chemical arts will recognize that the usefulness of the intermediates synthesized by the processes of this invention is not limited to the synthesis of the above-described antineoplastic agents.